PROJECT SUMMARY Retinitis pigmentosa (RP) is a group of genetic diseases in which one of multiple different mutations in one of more than 50 genes causes rod photoreceptor cell death. After most of the rods are eliminated, progressive death of cone photoreceptors occurs, resulting in gradual loss of visual field that can result in blindness. There are currently very few therapeutic options for RP, and the mechanism of cone cell death has been the subject of intense study. We and others have identified oxidative and nitrosative damage as key in the progressive loss of cone photoreceptors. We demonstrated that metipranolol, a nonselective ?-adrenergic receptor antagonist given orally for the treatment of arterial hypertension and topically for lowering intraocular pressure (IOP), also reduces nitrosative stress and promotes cone survival and function in the rd10 mouse model of RP. Importantly, topical administration 3x/day was more effective in preserving retinal function than daily subcutaneous injections. However, it is much easier to deliver drugs to the retina with conventional eye drops in mice than in larger eyes, and further, patients often do not adhere to dosing regimens requiring multiple doses each day. To this end, we have discovered an approach for effectively delivering drugs to the retina in large animals, including rabbits and pigs, with once daily topical eye drops. Our unique eye drop-based drug delivery technology provides improved intraocular delivery of both water soluble and water insoluble drugs, such as metipranolol. We hypothesize that a new hypotonic gelling eye drop formulation designed to maximize the residence time, intraocular penetration, and drug delivery to the retina with minimal toxicity will be an important step toward the development of a new once daily treatment for RP and other retinal degenerative disorders. With metipranolol?s established ocular safety and tolerability in humans, it is an ideal candidate for developing a first-of-its-kind eye drop for preserving vision in RP. In Specific Aim 1, we will develop and fully characterize new polymer blends for optimal viscosity, shear thinning, spreading, gelation rate, and intraocular penetration of metipranolol. In Specific Aim 2, we will test gelling formulations optimized for various key properties versus standard liquid eye drops in mouse and rat models of RP. In Specific Aim 3, we will evaluate ocular pharmacokinetics in pigs, which are considered the most relevant animal model to humans for topical eye drop dosing, as the eye size and structure is the most similar, and thus most relevant for characterizing delivery to the retina with a topical formulations. We will further evaluate ocular biocompatibility in rabbits, the most commonly used animal model to assess safety of ocular products due to the similarities in eye structure and the sensitivity of the eye to potential toxicity. If these preclinical studies progress as expected, we will be well-positioned for translation to the clinic.